ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.509C>T (p.Thr170Met) (rs779000871)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000662787 SCV001737915 likely benign Li-Fraumeni syndrome 1 2021-04-12 reviewed by expert panel curation This variant has been observed in 3 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). Transactivation assays show [retained/supertransactivation] function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). In summary, TP53 c.509C>T (p.Thr170Met) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS2_supporting; BS3_supporting.
Ambry Genetics RCV000163119 SCV000213630 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-27 criteria provided, single submitter clinical testing The p.T170M variant (also known as c.509C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 509. The threonine at codon 170 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in a patient diagnosed with an embryonal rhabdomyosarcoma of the testes at age 5; however, the family history did not resemble Li-Fraumeni syndrome and the parents were unavailable for testing (Magnusson, S et al. Pediatr Blood Cancer. 2012 Nov;59(5):846-53). This alteration was also seen in a penile carcinoma genome and IHC results on the tumor were consistent with altered p53 protein (Rocha, RM et al. Hum Pathol. 2012 Apr;43(4):481-8). This variant is in the DNA binding domain of the p53 protein and is reported to have partially functional transactivation capacity and is predicted to affect several p53 isoforms (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000206777 SCV000260532 uncertain significance Li-Fraumeni syndrome 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 170 of the TP53 protein (p.Thr170Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs779000871, ExAC 0.01%). This variant has been reported in individuals with hereditary breast cancer or rhabodomyosarcoma, with no family history of Li-Fraumeni or Li-Fraumeni-like syndrome (PMID: 31051129, 22653678). ClinVar contains an entry for this variant (Variation ID: 184014). This variant has been reported not to substantially affect TP53 protein function (PMID: 12826609, 30224644, 29979965). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000478196 SCV000567645 uncertain significance not provided 2018-03-13 criteria provided, single submitter clinical testing This variant is denoted TP53 c.509C>T at the cDNA level, p.Thr170Met (T170M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant was reported in a child with an embryonal rhabdomyosarcoma whose family history was not consistent with Li-Fraumeni or Li-Fraumeni-like syndrome (Magnusson 2012). TP53 Thr170Met is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). TP53 Thr170Met is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether TP53 Thr170Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000163119 SCV000686747 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-20 criteria provided, single submitter clinical testing
Counsyl RCV000662787 SCV000785596 uncertain significance Li-Fraumeni syndrome 1 2017-10-02 criteria provided, single submitter clinical testing

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